Department of Neuroscience, Imaging, and Clinical Sciences and Center for Research on Aging and Translational Medicine, "G. d'Annunzio" University School of Medicine, Chieti, Italy (A.Sa., A.B., A.C., M.D., S.T., P.G.-L., T.S., L.D.F., R.F., P.B., S.A., P.P.); Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (E.R., G.A.F.); Departments of General Pathology (V.A., A.Sg.) and Pharmacology (C.P.), Catholic University School of Medicine, Rome, Italy; Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China (G.L., Y.G.); and Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (Y.Y.).
Department of Neuroscience, Imaging, and Clinical Sciences and Center for Research on Aging and Translational Medicine, "G. d'Annunzio" University School of Medicine, Chieti, Italy (A.Sa., A.B., A.C., M.D., S.T., P.G.-L., T.S., L.D.F., R.F., P.B., S.A., P.P.); Department of Systems Pharmacology and Translational Therapeutics and Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania (E.R., G.A.F.); Departments of General Pathology (V.A., A.Sg.) and Pharmacology (C.P.), Catholic University School of Medicine, Rome, Italy; Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China (G.L., Y.G.); and Department of Pharmacology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China (Y.Y.)
J Pharmacol Exp Ther. 2019 Sep;370(3):416-426. doi: 10.1124/jpet.119.259382. Epub 2019 Jun 27.
Inflammatory bowel disease (IBD) is associated with an increased risk for thromboembolism, platelet activation, and abnormalities in platelet number and size. In colitis, platelets can extravasate into the colonic interstitium. We generated a mouse with a specific deletion of cyclooxygenase (COX)-1 in megakaryocytes/platelets [(COX-1 conditional knockout (cKO)] to clarify the role of platelet activation in the development of inflammation and fibrosis in dextran sodium sulfate (DSS)-induced colitis. The disease activity index was assessed, and colonic specimens were evaluated for histologic features of epithelial barrier damage, inflammation, and fibrosis. Cocultures of platelets and myofibroblasts were performed. We found that the specific deletion of COX-1 in platelets, which recapitulated the human pharmacodynamics of low-dose aspirin, that is, suppression of platelet thromboxane (TX)A production associated with substantial sparing of the systemic production of prostacyclin, resulted in milder symptoms of colitis, in the acute phase, and almost complete recovery from the disease after DSS withdrawal. Reduced colonic accumulation of macrophages and myofibroblasts and collagen deposition was found. Platelet-derived TXA enhanced the ability of myofibroblasts to proliferate and migrate in vitro, and these effects were prevented by platelet COX-1 inhibition or antagonism of the TXA receptor. Our findings allow a significant advance in the knowledge of the role of platelet-derived TXA in the development of colitis and fibrosis in response to intestinal damage and provide the rationale to investigate the potential efficacy of the antiplatelet agent low-dose aspirin in limiting the inflammatory response and fibrosis associated with IBD. SIGNIFICANCE STATEMENT: Inflammatory bowel disease (IBD) is characterized by the development of a chronic inflammatory response, which can lead to intestinal fibrosis for which currently there is no medical treatment. Through the generation of a mouse with specific deletion of cyclooxygenase-1 in megakaryocytes/platelets, which recapitulates the human pharmacodynamics of low-dose aspirin, we demonstrate the important role of platelet-derived thromboxane A in the development of experimental colitis and fibrosis, thus providing the rationale to investigate the potential efficacy of low-dose aspirin in limiting the inflammation and tissue damage associated with IBD.
炎症性肠病（IBD）与血栓栓塞、血小板活化以及血小板数量和大小异常的风险增加有关。在结肠炎中，血小板可以渗出到结肠间质中。我们生成了一种巨核细胞/血小板中特异性缺失环氧化酶（COX）-1 的小鼠[COX-1 条件性敲除（cKO）]，以阐明血小板活化在葡聚糖硫酸钠（DSS）诱导的结肠炎中炎症和纤维化发展中的作用。评估疾病活动指数，并评估结肠标本上皮屏障损伤、炎症和纤维化的组织学特征。进行血小板和肌成纤维细胞的共培养。我们发现，血小板中 COX-1 的特异性缺失，模拟了低剂量阿司匹林的人体药效动力学，即抑制血小板血栓素（TXA）A 的产生，同时大量保留了全身前列腺素的产生，导致结肠炎的症状较轻，在急性期，并且在 DSS 停药后几乎完全从疾病中恢复。发现结肠巨噬细胞和肌成纤维细胞的积累减少，胶原沉积减少。血小板衍生的 TXA 增强了肌成纤维细胞在体外增殖和迁移的能力，而这些作用可通过血小板 COX-1 抑制或 TXA 受体拮抗来预防。我们的发现使人们对血小板衍生的 TXA 在肠道损伤后发展为结肠炎和纤维化中的作用有了重大的了解，并为研究抗血小板药物低剂量阿司匹林在限制与 IBD 相关的炎症反应和纤维化方面的潜在疗效提供了依据。
炎症性肠病（IBD）的特征是慢性炎症反应的发展，这可能导致目前尚无医学治疗方法的肠道纤维化。通过生成一种巨核细胞/血小板中特异性缺失环氧化酶-1 的小鼠，模拟低剂量阿司匹林的人体药效动力学，我们证明了血小板衍生的血栓素 A 在实验性结肠炎和纤维化发展中的重要作用，从而为研究低剂量阿司匹林在限制与 IBD 相关的炎症和组织损伤方面的潜在疗效提供了依据。
